Brain dysfunction and thyroid antibodies: autoimmune diagnosis and misdiagnosis

Abstract

Hashimoto encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis, has been defined by sub-acute onset encephalopathy, with elevated thyroid antibodies, and immunotherapy responsiveness, in the absence of specific neural autoantibodies. We aimed to retrospectively review 144 cases referred with suspected Hashimoto encephalopathy over a 13-year period, and to determine the clinical utility of thyroid antibodies in the course of evaluation of those patients. One hundred and forty-four patients (all thyroid antibody positive) were included; 72% were women. Median age of symptom onset was 44.5 years (range, 10-87). After evaluation of Mayo Clinic, 39 patients (27%) were diagnosed with an autoimmune CNS disorder [autoimmune encephalopathy (36), dementia (2) or epilepsy (1)]. Three of those 39 patients had neural-IgGs detected (high glutamic acid decarboxylase-65, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-receptor and neural-restricted unclassified antibody), and 36 were seronegative. Diagnoses among the remaining 105 patients (73%) were functional neurological disorder (<i>n</i> = 20), neurodegenerative disorder (<i>n</i> = 18), subjective cognitive complaints (<i>n</i> = 14), chronic pain syndrome (<i>n</i> = 12), primary psychiatric (<i>n</i> = 11), sleep disorder (<i>n</i> = 10), genetic/developmental (<i>n</i> = 8), non-autoimmune seizure disorders (<i>n</i> = 2) and other (<i>n</i> = 10). More patients with autoimmune CNS disorders presented with sub-acute symptom onset (<i>P</i> < 0.001), seizures (<i>P</i> = 0.008), stroke-like episodes (<i>P</i> = 0.007), aphasia (<i>P</i> = 0.04) and ataxia (<i>P</i> = 0.02), and had a prior autoimmune history (<i>P</i> = 0.04). Abnormal brain MRI (<i>P</i> = 0.003), abnormal EEG (<i>P</i> = 0.007) and CSF inflammatory findings (<i>P</i> = 0.002) were also more frequent in the autoimmune CNS patients. Patients with an alternative diagnosis had more depressive symptoms (<i>P</i> = 0.008), anxiety (<i>P</i> = 0.003) and chronic pain (<i>P</i> = 0.002). Thyoperoxidase antibody titre was not different between the groups (median, 312.7 versus 259.4 IU/ml; <i>P</i> = 0.44; normal range, <9 IU/ml). None of the non-autoimmune group and all but three of the CNS autoimmune group (two with insidious dementia presentation, one with seizures only) fulfilled the autoimmune encephalopathy criteria proposed by Graus <i>et al.</i> (A clinical approach to diagnosis of autoimmune encephalitis. <i>Lancet Neurol</i> 2016; 15: 391-404.) (sensitivity, 92%; specificity, 100%). Among patients who received an immunotherapy trial at our institution and had objective post-treatment evaluations, the 16 responders with autoimmune CNS disorders more frequently had inflammatory CSF, compared to 12 non-responders, all eventually given an alternative diagnosis (<i>P</i> = 0.02). In total, 73% of the patients referred with suspected Hashimoto encephalopathy had an alternative non-immune-mediated diagnosis, and more than half had no evidence of a primary neurological disorder. Thyroid antibody prevalence is high in the general population, and does not support a diagnosis of autoimmune encephalopathy in the absence of objective neurological and CNS-specific immunological abnormalities. Thyroid antibody testing is of little value in the contemporary evaluation and diagnosis of autoimmune encephalopathies.